|
Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 15, Number 6, 2009
Contents
Exploiting Multivalency in Drug Design
Executive Editor: Diego Muñoz-Torrero
Editorial: Pp. 585-586
Designing Multiple Ligands – Medicinal Chemistry Strategies
and Challenges Pp. 587-600
R. Morphy and Z. Rankovic
[Abstract] [Purchase Article] [PMID: 19199984 PubMed - indexed for MEDLINE]
MTDL Design Strategy in the Context of Alzheimer’s
Disease: From Lipocrine to Memoquin and Beyond Pp.
601-613
M.L. Bolognesi, M. Rosini, V. Andrisano,
M. Bartolini, A. Minarini, V. Tumiatti and C. Melchiorre
[Abstract] [Purchase Article] [PMID: 19199985 PubMed - indexed for MEDLINE]
Pharmacodynamic Hybrids Coupling Established
Cardiovascular Mechanisms of Action with Additional Nitric
Oxide Releasing Properties Pp. 614-636
A. Martelli, M.C. Breschi and V.
Calderone
[Abstract] [Purchase Article] [PMID: 19199986 PubMed - indexed for MEDLINE]
Multivalent & Multifunctional Ligands
to β-Amyloid
Pp. 637-658
Y.S. Kim, J.H. Lee, J. Ryu and
D.J. Kim
[Abstract] [Purchase Article] [PMID: 19199987 PubMed - indexed for MEDLINE]
Novel Classes of Dimer Antitumour Drug Candidates Pp.
659-674
L.M.C. Chow and T.H. Chan
[Abstract] [Purchase Article] [PMID: 19199988 PubMed - indexed for MEDLINE]
Designer Peptides: Learning from Nature Pp.
675-681
A. Shrivastava, A.D. Nunn and M.F.
Tweedle
[Abstract] [Purchase Article] [PMID: 19199989 PubMed - indexed for MEDLINE]
Design of Multivalent Ligand Targeting G-Protein-Coupled Receptors
Pp. 682-718
Z. Liu, J. Zhang and A. Zhang
[Abstract] [Purchase Article] [PMID: 19199990 PubMed - indexed for MEDLINE]
Multivalent-Based Drug Design Applied to Serotonin
5-HT4 Receptor Oligomers Pp. 719-729
F. Lezoualc’h, R. Jockers and
I. Berque-Bestel
[Abstract] [Purchase Article] [PMID: 19199991 PubMed - indexed for MEDLINE]
Abstracts
[Back to top]
Editorial: Exploiting Multivalency in Drug Design
Structural manipulation of already marketed drugs,
or in general, of known biologically active compounds as a
means to get novel drug candidates with improved profiles
constitutes a widespread practice in medicinal chemistry.
In most cases, from this approach arise novel molecules with
a degree of structural complexity similar to that of the parent
compound and containing a single pharmacophoric moiety aimed
at hitting a single biological target. Another way to get
access to novel drug candidates from known drugs that is attracting
an ever-expanding interest involves the combination of more
than one identical or different pharmacophores rather than
the structural modificacion of a single one. This approach
results in, obviously more complex, dimeric or hybrid drug
candidates with significantly distinct pharmacological profiles
relative to the monomeric parent compounds from which they
were designed. Thus, combination into a single framework of
carefully selected different pharmacophoric moieties can endow
the resulting hybrid molecule with the ability to interact
with different biological targets, thereby leading to a sequential
interference at different levels of a given pathogenic pathway
or to a series of complementary pharmacological effects, and,
consequently to an enhanced efficiency in the management of
that particular disease. Also, hybrid and dimeric drug candidates
can be rationally designed to provide multivalent interactions
with biological targets having more than one binding site
or even with targets which are themselves oligomeric, thus
affording a dramatically increased affinity.
In this issue, the rationale for the design of representative
examples of different classes of multivalent dimeric and hybrid
drug candidates is discussed, as well as the advantages they
provide over their monomeric counterparts in different therapeutic
areas.
Complex diseases constitute a scenario where multi-target
hybrid molecules could afford a level of effectiveness not
attainable by selective single-target drugs. Reaching far
beyond the lifetime of Paul Ehrlich was his conviction that
some particular compounds could be developed to act as selective
magic bullets against a specific disease agent without harming
the patient with a given disease. The resulting one-molecule,
one-target paradigm has driven drug discovery in the pharmaceutical
industry in the last decades, along with the increasing knowledge
about the molecular mechanisms underlying common diseases
and the identification of particular biological targets involved
in the pathogenesis of the disease. This approach is still
valid and, indeed the one-target, one-disease philosophy remains
the main strategy in most pharmaceutical companies. However,
complex diseases such as cancer, cardiovascular diseases,
inflammatory diseases, neurological disorders, diabetes or
asthma, among others, result from multiple molecular defects,
and therefore involve more than one key pathogenic target.
The polyetiological origin of complex diseases makes untenable
the notion that they can be efficiently managed through drugs
hitting a single target. Consequently, research efforts in
this field are gradually shifting towards the rational design
of drug candidates aimed at hitting multiple biological targets.
The development of hybrid drug candidates which combine more
than one pharmacophore to hit more than one target involved
in the pathogenesis of given complex diseases is discussed
in Chapters 1?4. In Chapter 1, Drs. Morphy and Rankovic [1]
provide a general overview of the current strategies for the
design of hybrid drug candidates with a multi-target profile,
with examples in different therapeutic areas. They also discuss
the challenge which represent to medicinal chemists the optimization
of the activity profile of such compounds, including the fine
tuning of the desired activities or the designing out of undesired
activities, as well as the optimization of physicochemical
and pharmacokinetic properties, particularly to ensure a good
oral bioavailability, sometimes compromised due to the large
size of hybrid molecules combining more than one pharmacophore.
In Chapter 2, Drs. Bolognesi and Melchiorre, and colleagues
[2] present an exciting review showing the successful evolution
of a series of multi-target-directed-ligands to modulate an
increasing number of biological targets involved at different
levels of the neurotoxic cascade of Alzheimer’s disease,
which eventually has led to a proof-of-concept of the multi-target
approach with one of the resulting drug candidates. In general,
hybrid molecules designed from bridging two pharmacophores
in a single molecule are intended to be metabolically irreversible,
thus being capable of interacting with both targets through
the two ends of the molecule. However, in some cases multi-target
hybrid compounds are designed to be metabolically cleaved
to release in vivo the two constituting pharmacophores,
which would then independently interact with each biological
target. This is the case for a number of nitric oxide (NO)-releasing
hybrids which combine a pharmacophore aimed at hitting a classical
target involved in cardiovascular diseases with a NO donor
moiety, intented to increase the efectiveness of the drug
and/or to reduce adverse side effects, due to the beneficial
complementary cardiovascular effects conferred by NO. The
main classes of such NO-donor hybrids are reviewed in Chapter
3 by Dr. Calderone and colleagues [3]. In Chapter 4, Dr. Kim
and colleagues [4] present some examples of hybrid compounds
which combine a pharmacophore to bind to the β-amyloid
peptide (Aβ),
the key triggering molecule in Alzheimer’s disease,
and an additional pharmacophore conferring a complementary
action. They also present some examples of dimeric Aβ
ligands, of interest mainly as imaging probes for Alzheimer’s
disease, endowed with greater Aβ
binding affinities relative to the monomeric counterparts,
due to their ability to bind to two different binding sites
within Aβ
fibrils. The increase in affinity is a general feature of
multivalent compounds which simultaneously bind to more than
one binding site of a given biological target, a kind of interaction
which occurs throughout biological systems. In Chapter 5,
Drs. Chow and Chan [5] discuss how this strategy has been
exploited to render high affinity antitumour drug candidates,
presenting several classes of dimeric and hybrid molecules
designed to interact bivalently with some biological targets
involved in cancer or in multidrug resistance in cancer cells
such as DNA, proteasome or P-glycoprotein. In Chapter 6, Dr.
Tweedle and colleagues [6] summarize the progress in the development
of high affinity hetero-multimeric peptides, designed by linking
peptides to simultaneously bind to different sites of a single
biological target (receptor tyrosine kinases), for targeted
therapies and diagnostics. A particularly interesting kind
of multivalent interaction is that established between a multivalent
compound and a dimeric or oligomeric receptor. Receptor dimerization
or oligomerization, which is a common feature of G protein-coupled
receptors (GPCRs), has driven the design of bivalent ligands
targeting two receptor members in the oligomerized complex,
in an attempt to improve affinity, potency and receptor subtype
selectivity. In Chapter 7, Dr. Zhang and colleagues [7] comprehensively
review the evidences for the heteromerization of different
types and subtypes of GPCRs and the design of a large number
of bivalent drug candidates which target such receptor oligomers.
In Chapter 8, Dr. Berque-Bestel and colleagues [8] present
an exciting review in which the key determinants in the design
of bivalent dimeric or hybrid ligands are discussed, including
a nice example of rational design of dimeric compounds targeting
a specific GPCR, namely the 5-HT4
receptor dimer.
The multi-target / multivalent approaches to drug design have
opened new avenues for the management of particular diseases,
and, indeed an increasing number of dimeric and hybrid drug
candidates arising from such approaches are entering clinical
trials. If they prove successful in the clinic, this will
certainly drive much more research efforts towards this kind
of approaches.
References
[1] Morphy R, Rankovic Z. Designing Multiple Ligands −
Medicinal Chemistry Strategies and Challenges. Curr Pharm
Des 2009; 15(6): 587-600.
[2] Bolognesi ML, Rosini M, Andrisano V, Bartolini M, Minarini
A, Tumiatti V, Melchiorre C. MTDL Design Strategy in the Context
of Alzheimer’s Disease: from Lipocrine to Memoquin and
Beyond. Curr Pharm Des 2009; 15(6): 601-613.
[3] Martelli A, Breschi MC, Calderone V. Pharmacodynamic Hybrids
Coupling Established Cardiovascular Mechanisms of Action with
Additional Nitric Oxide Releasing Properties. Curr Pharm Des
2009; 15(6): 614-636.
[4] Kim YS, Lee JH, Ryu J, Kim DJ. Multivalent & Multifunctional
Ligands to β-Amyloid.
Curr Pharm Des 2009; 15(6): 637-658
[5] Chow LMC, Chan TH. Novel Classes of Dimer Antitumour Drug
Candidates. Curr Pharm Des 2009; 15(6): 659-674.
[6] Shrivastava A, Nunn AD, Tweedle MF. Designer Peptides:
Learning from Nature. Curr Pharm Des 2009; 15(6): 675-681.
[7] Liu Z, Zhang J, Zhang A. Design of Multivalent Ligand
Targeting G-Protein-Coupled Receptors. Curr Pharm Des 2009;
15(6): 682-718.
[8] Lezoualc’h F, Jockers R, Berque-Bestel I. Multivalent-Based
Drug Design Applied to Serotonin 5-HT4
Receptor Oligomers. Curr Pharm Des 2009; 15(6): 719-729.
Diego Muñoz-Torrero
Professor
Laboratori de Química Farmacèutica
Facultat de Farmàcia
Universitat de Barcelona
Av. Diagonal, 643
08028-Barcelona
Spain
Tel: (34) 93 402 45 33
Fax: (34) 93 403 59 41
E-mail: dmunoztorrero@ub.edu
[Back to top]
[Purchase Article] [PMID: 19199984 PubMed - indexed for MEDLINE]
Designing Multiple Ligands – Medicinal Chemistry Strategies
and Challenges
R. Morphy and Z. Rankovic
It has been widely recognised over the recent years that
parallel modulation of multiple biological targets can be
beneficial for treatment of diseases with complex etiologies
such as cancer asthma, and psychiatric disease. In this article,
current strategies for the generation of ligands with a specific
multi-target profile (designed multiple ligands or DMLs) are
described and a number of illustrative example are given.
Designing multiple ligands is frequently a challenging endeavour
for medicinal chemists, with the need to appropriately balance
affinity for 2 or more targets whilst obtaining physicochemical
and pharmacokinetic properties that are consistent with the
administration of an oral drug. Given that the properties
of DMLs are influenced to a large extent by the proteomic
superfamily to which the targets belong and the lead generation
strategy that is pursued, an early assessment of the feasibility
of any given DML project is essential.
[Back to top]
[Purchase Article] [PMID: 19199985 PubMed - indexed for MEDLINE]
MTDL Design Strategy in the Context of Alzheimer’s Disease:
From Lipocrine to Memoquin and Beyond
M.L. Bolognesi, M. Rosini, V. Andrisano,
M. Bartolini, A. Minarini, V. Tumiatti and C. Melchiorre
The multifunctional nature of Alzheimer’s disease
(AD) provides the logical foundation for the development of
an innovative drug design strategy centered on multi-target-directed-ligands
(MTDLs). In recent years, the MTDL concept has been exploited
to design different ligands hitting different biological targets.
Our first rationally designed MTDL was the polyamine caproctamine
(1), which provided a synergistic cholinergic
action against AD by antagonizing muscarinic M2
autoreceptors and inhibiting acetylcholinesterase (AChE).
Lipocrine (7) represented the next step in
our research. Due to its ability to inhibit AChE catalytic
and non-catalytic functions together with oxidative stress,
7 emerged as an interesting pharmacological
tool for investigating the neurodegenerative mechanism underlying
AD. Memoquin (9) is a quinone-bearing polyamine
endowed with a unique multifunctional profile. With its development,
we arrived at the proof of concept of the MTDL drug discovery
approach. Experiments in vitro and in vivo
confirmed its multimodal mechanisms of action and its interaction
with different end-points of the neurotoxic cascade leading
to AD. More recently, the MTDL approach led to carbacrine
(12). In addition to the multiple activities
displayed by 7, 12 displayed
an interesting modulation of NMDA receptor activity. The pivotal
role played by this target in AD pathogenesis suggests that
12 may be a promising new chemical entity
in the MTDL gold rush.
[Back to top]
[Purchase Article] [PMID: 19199986 PubMed - indexed for MEDLINE]
Pharmacodynamic Hybrids Coupling Established Cardiovascular
Mechanisms of Action with Additional Nitric Oxide Releasing
Properties
A. Martelli, M.C. Breschi and V.
Calderone
The pharmacotherapy of complex pathological states at
the cardiovascular level often requires different and complementary
pharmacodynamic properties. This is frequently achieved through
the administration of “cocktails”, composed by
several drugs possessing different mechanisms of action. In
the last years, a revision of the “one-compound-one-target”
paradigm led to a wide development of new classes of molecules,
possessing more pharmacological targets. Among them, this
innovative strategy produced interesting hybrid drugs, with
a dual mechanism of action: a) a fundamental and well-established
pharmacodynamic profile and b) the release of nitric oxide
(NO), playing a pivotal role in the modulation of the function
of cardiovascular system, where it induces vasorelaxing and
antiplatelet responses.
These new pharmacodynamic hybrids present the advantage of
adding to a main mechanism of action (for example, cyclooxygenase
inhibition, beta-antagonism or ACE-inhibition) also a slow
release of NO, useful either to reduce the adverse side effects
and/or to improve the effectiveness of the drug.
This review presents the chemical features of many examples
of NO-releasing hybrids of cardiovascular drugs and explains
the pharmacological improvements conferred by the addition
of such NO-donor properties.
[Back to top]
[Purchase Article] [PMID: 19199987 PubMed - indexed for MEDLINE]
Multivalent & Multifunctional Ligands to β-Amyloid
Y.S. Kim, J.H. Lee, J. Ryu and
D.J. Kim
Ligands selectively targeting β-amyloid
in the living brain are promising candidates of therapeutics
and early diagnosis tools for Alzheimer’s disease. Among
the major stages of β-amyloid
aggregation, monomers and oligomers are excellent targets
to reduce neurotoxic brain damages for prevention of the disease
progression, while oligomers and fibrils, abundant in the
late stage of the disease, are pathological objectives to
develop reliable imaging probes. So far, there have been many
efforts to develop a wide variety of monovalent β-amyloid
ligands such as thioflavin T, PIB, FDDNP, curcumin, and tramiprosate.
However, pathology of Alzheimer’s disease is not fully
understood yet so that there is currently no cure and further
investigations on Alzheimer’s disease are needed. For
past several years, multivalent β-amyloid
ligands have offered an alternative route by enhancing binding
affinity of drug candidates. In addition, it has been revealed
that not only neurotoxicity due to the protein misfolding
but also other factors are involved in the β-amyloid
cascade such as oxidative stress, inflammation, metal chelation,
and several types of neurotransmitters. Thus, there have been
numerous studies to improve binding affinities of single β-amyloid
ligands via adopting multivalent effects or to develop
drug candidates targeting multiple stages of the pathological
cascade. In this review, multivalent and multifunctional β-amyloid
ligands and their promising aspects as an alternative approach
to Alzheimer’s disease are discussed.
[Back to top]
[Purchase Article] [PMID: 19199988 PubMed - indexed for MEDLINE]
Novel Classes of Dimer Antitumour Drug Candidates
L.M.C. Chow and T.H. Chan
Polyvalency in the biological world is defined as the
simultaneous binding of multiple ligands to one receptor.
Polyvalency can increase the affinity of the polyvalent ligand
by 100-1000 fold over the monovalent ligand. Such phenomenon
has been employed to design polyvalent toxin inhibitors. Bivalency
is a similar approach where two ligands are joined together
with a linker to form a homo- or hetero-dimer with an increase
in affinity by up to several hundred fold over the monovalent
ligand. This review will summarize the recent advancement
in designing bivalent inhibitors to be used as antitumour
agents. Some dimers (e.g. artemisinin homo-dimer) simply increase
the affinity of the monovalent ligands without detailed knowledge
of the target. Other dimers are designed with well-characterized
targets, for example, jesterone dimer (inhibiting Rel/NF-κB)
and 3,3’-diindolymethane and their derivatives (inhibiting
Akt and NFκB).
Some dimers are designed based on the high definition structure
between ligand and target (e.g. benzodiazepine and daunorubi-cin
interacting with DNA). Heterodimers have also been produced
by combining either two different antitumor drugs (e.g. cis-platin/acridine
or cis-platin/naphthalimide) or combining one antitumor
candidate (artemisinin) with a molecule which can increase
the efficacy of the former (transferrin receptor). Finally
we will discuss the design of bivalent inhibitors of the P-glycoprotein
(ABCB1; MDR or P-gp) to overcome the problem of antitumor
resistance.
[Back to top]
[Purchase Article] [PMID: 19199989 PubMed - indexed for MEDLINE]
Designer Peptides: Learning from Nature
A. Shrivastava, A.D. Nunn and M.F.
Tweedle
Recent advances in designing peptide ligands for therapeutic
targets are making peptides an attractive alternative to small
molecules and proteins. It is now common to see peptides developed
with affinities comparable to antibodies and specificities
much better than small molecules or antibodies. This is especially
true in the case of tumor targeting cytotoxic drugs or targeted
diagnostics where peptides can be used as a delivery vehicle
for drugs or diagnostics. Moreover, lessons learned from nature
in understanding peptide ligands are proving to be useful
in designing better antibodies and small molecule therapeutics.
[Back to top]
[Purchase Article] [PMID: 19199990 PubMed - indexed for MEDLINE]
Design of Multivalent Ligand Targeting G-Protein-Coupled Receptors
Z. Liu, J. Zhang and A. Zhang
More and more evidences are still accumulating rapidly
on the G-protein-coupled-receptors (GPCRs) dimerization/oligomerization.
Such common feature of GPCRs has called extensive attention
to both pharmacologists and medicinal chemists for illustration
of the pharmacological functions and therapeutic utilities
of such receptor complex. Although there is still no clear
explanation for the receptor dimerization/oligomerization,
a large number of multivalent ligands (MLs) have been designed
to target the receptor-dimers/oligomers. Such MLs have gained
much acceptance in exploring the receptor complex of dopaminergic,
adrenergic, serotoninergic, and opioidic receptor systems,
due to the relatively broader experience in recognizing the
receptor-dimerization. More and more MLs have also been designed
to face GPCR-related very complex neurodegenerative diseases,
such as Parkinson’s disease (PD), Alzheimer’s
disease (AD) and schizophrenia, which are not effectively
treated by traditional highly selective drugs. Herein, some
of the most recent developments in this field, as well as
some typical examples of MLs, are highlighted, with a particular
focus on GPCRs.
[Back to top]
[Purchase Article] [PMID: 19199991 PubMed - indexed for MEDLINE]
Multivalent-Based Drug Design Applied to Serotonin 5-HT4
Receptor Oligomers
F. Lezoualc’h, R. Jockers and
I. Berque-Bestel
Historically treated as monomeric polypeptides, G protein-coupled
receptors (GPCRs) have been shown to exist and function as
constitutively formed dimers or oligomers. The quaternary
structure of GPCRs may modulate ligand binding properties
through allosteric mechanisms offering new opportunities for
drug design by exploiting multivalency. In this context, multivalent
ligands versus bivalent-ligands, possessing two binding
motifs connected by a linker, have been investigated and have
revealed striking differences in their functional properties
compared to their monovalent counterparts. These bi-functional
drugs, which are able to activate the two protomers in a dimer
simultaneously, emerge as novel and promising drugs for a
variety of multi-factorial diseases.
In this review, key requirements for the successful design
and synthesis of GPCR multivalent ligands composed of pharmacophores
and a linker will be discussed. We will then focus on the
5-HT4 receptor (5-HT4R),
whose ligands emerged as promising drugs for a variety of
central nervous disorders. Upon description of biochemical
and biophysical evidences of 5-HT4R
dimerization, we will present the multivalent ligand approach,
which was assisted by molecular docking experiments on the
5-HT4R dimer model.
|
